2007 ACR CME Activity - Day Two
CME Information
Accreditation Statement: The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit Designation: The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.
The Johns Hopkins University School of Medicine takes responsibility for the content, quality and scientific integrity of this CME activity
Educational Goal: To help address the unmet needs between current knowledge and its application in patient care, the Highlights from the 71st Annual ACR Meeting: A Continuing Education Series seeks to provide rheumatologists and to other related healthcare professionals with the latest clinical information and data from the 71st Annual American College of Rheumatology Meeting.
Learning Objectives: At the conclusion of this activity, participants should be able to:
- Discuss key data being presented at the annual ACR meeting in a manner that is practical and clinically relevant.
- Assess how biologics can be incorporated into appropriate therapeutic strategies based on their different mechanisms of actions, response rates, frequency of administrations and safety and tolerability profiles.
- Recognize the long-term implications of biologic therapy on joint stability and mobility, cardiovascular complications and other risk factors.
Release Date: November 28, 2007
Expiration Date: November 28, 2008
Estimated time for completion: 30 minutes
Target Audience: This activity is intended for rheumatologists and relatedhealthcare professionals. There are no prerequisites for participants.
Faculty and Qualifications:
- Alan Baer, MD, Associate Professor of Medicine and Director, Johns Hopkins University Clinical Practice at Good Samaritan Hospital, Chief of Rheumatology at Good Samaritan Hospital
- Jon T. Giles, MD, Assistant Professor of Medicine, Division of Rheumatology, Department of Medicine, Johns Hopkins University
- Vicky Ruffing, RN, Nurse Manager, Johns Hopkins Arthritis Center
Disclosure Statements: As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed of any commercial product(s) discussed in an educational presentation. The presenting faculty reported the following:
- Alan Baer, MD - Dr. Baer has no financial relationships to disclose.
- Jon T. Giles, MD – Dr. Giles discloses the following: Grants/Research Support: Roche, Centocor; Consultant: Abbott Laboratories; Honorarium: Prous Science, Amgen.
- Vicky Ruffing, RN – Ms. Ruffing discloses the following:Consultant for Roche, Amgen, Genentech, BMS, and Abbott
Off-Label Statement: No faculty member has indicated that their presentation will include information on off-label products.
Disclaimer: The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contradictions, warnings and adverse effects before administering pharmacologic therapy to patients.
Method of Participation: In order to receive your certificate follow the link to the post-test, achieve a score of at least 70 percent and complete the program evaluation. Upon successful completion follow the directions to print your certificate.This activity is designed to be completed within the time designated; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period.
INTRODUCTION: Insights Into Pathophysiology, Diagnosis, and Treatment
The ACR/ARHP annual scientific meeting is the largest world meeting of physicians, allied health care professionals, and researchers focused on improving outcomes for people with rheumatic diseases. There were several important presentations that further elucidate the pathophysiologic mechanisms in rheumatic diseases, improve diagnostic parameters, describe new treatment options, and describe risk factors for adverse events (AEs). “Highlights from the 71st Annual American College of Rheumatology Meeting: A Continuing Education Series” presents practitioners with a practical summary of key data presented at the conference. This issue highlights new insights into the pathogenesis, diagnosis, and treatment of several systemic rheumatic diseases presented on Thursday, November 8, and Friday, November 9, 2007.
DAY 2: Role Of IL-17 in the Pathophysiology of Rheumatologic Diseases
Signaling through interleukin 17 (IL-17) mediates a variety of proinflammatory responses, yet the role of this cytokine in the initiation and pathogenesis of autoimmunity is not well understood. Several studies shed light on the importance of the T-helper 17 (Th17) lineage of T-cells, which produce IL-17, in the pathogenesis of various rheumatic diseases.
The IL-23/IL-17 Axis: Evidence for a Novel Mechanism of Inflammation (1)
Dr. Robert Colbert presented results of a study in an animal model (HLA-B27/human β2m transgenic [B27-Tg] rats) of spondyloarthritis (SpA) that established a new link among HLA-B27 (a class I MHC molecule on the surface of leukocytes) the unfolded protein response (UPR) and inflammation. This study showed that HLA-B27 misfolding, in which newly formed heavy chains bind together and clump in the endoplasmic reticulum (ER), leads to ER stress and activates an unfolded protein response. This leads to increased production of IL-23 by macrophages and ultimately to upregulation of Th17 CD4+ T-cells relative to Th-1 cells and increased expression of IL-17. Increased levels of IL-17 were seen in the colon and mesenteric lymph nodes in association with colitis. These results provide insight to the pathogenesis of SpA and suggest new therapeutic targets.
Wegener’s Granulomatosis
Wegener’s granulomatosis is a form of vasculitis that affects the lungs, kidneys and other organs. It is part of a larger group of vasculitic syndromes that all feature the presence for an abnormal type of circulating antibody termed ANCAs (antineutrophil cytoplasmic antibodies) and affect small and medium-sized blood vessels. The following presentations were selected to describe emerging data on transplantation and the role of Th-17 in WG.
Renal Graft Survival and Patient Mortality in WG: A Case/Control Study (2)
Renal transplantation has emerged as an important treatment advance for patients with WG and microscopic polyangiitis who have developed end-stage renal disease (ESRD).
Dr. Curry Koening and colleagues reviewed the United States Renal Data System (USRDS) to compare renal graft survival and patient mortality rates in patients undergoing first transplant for WG (n = 712) or other causes of ESRD (n = 1424) between 1988 and 2004. Cases were matched to 2 controls by gender, race, and age at transplant (+/- 2 years), year of transplant (+/- 2 years), allograft type, and total number of transplants. The mean age was 44.3 years with 53% of both groups receiving cadaveric grafts. The results showed:
- 158 (22%) grafts failed in WG patients compared to 366 (26%) in controls (P = .04)
- Chronic rejection was the most common cause of graft failure in both groups; recurrent disease occurred in 4.4% of both groups
- Allograft survival rates at 6 months, 1 year, and 5 years were:
- WG: 94.4% (95% CI 92.4-95.8), 93.8% (91.8-95.3), 86.9% (84.2-89.2)
- Controls: 94.1% (95% CI 92.7-95.2), 92.6% (91.1-93.9), 82.7% (80.6-84.6)
- A total of 137 (19%) WG patients died compared to 361 (25%) in controls (P = .002)
- Infection was the most common cause of death in WG patients (n = 29, 21%) compared to myocardial infarction (MI) or stroke in 65 (18%) of controls
- Patient survival rates at 6 months, 1 year, and 5 years were:
- WG: 97.1% (95% CI 95.5-98.1), 95.9% (94.2-97.2), 89.9% (87.4-91.9)
- Control: 96.7% (95% CI 95.6-97.5), 95.2% (93.9-96.2), 85.7% (83.7-87.4)
In summary, patients undergoing renal transplant for WG had a lower rate of graft failure and mortality than patients transplanted for other causes, and graft failure due to recurrent disease was an uncommon cause of graft loss.
Circulating Pr3-specific T-helper-17 Cells in Wegener’s Granulomatosis (3)
This study compared the Th cell response of 26 patients with Wegener’s granulomatosis (WG) and 10 healthy controls.
- WG patients demonstrated a blunted response to various antigens when compared with healthy control patients.
- WG patients had an enhanced Th2 and Th17 response to antigen exposure.
- The Th1 response did not differ between WG patients and healthy controls.
- Proteinase-3 (PR3)-ANCA positive patients had an increased frequency of PR3-specific Th17 cells.
These data indicate that Th17 plays an important role in WG and may represent a new treatment target.
Diagnosis of Giant Cell Arteritis
The diagnosis of giant cell arteritis (GCA) is based on characteristic histopathologic features in an affected vessel, usually the temporal artery. Because these features are not uniformly distributed throughout the vessel, the temporal artery biopsy has a false negative rate of approximately 10%. This rate can be potentially reduced by taking longer sections of temporal artery or resecting portions of the temporal arteries on both sides of the head.
Effect of Biopsy Length and Bilateral Sampling on the Rate of Positive Temporal Artery Biopsies (4)
Dr. Gabriel Breuer and colleagues investigated the relationship between temporal artery biopsy (TAB) length and the diagnostic sensitivity for GCA. TAB was considered positive if there was a mononuclear cell infiltrate in the vessel wall. Biopsy-negative GCA was diagnosed when patients fulfilled the ACR criteria and had a rapid response to steroid therapy. Patients were divided into 3 groups: biopsy-positive GCA, biopsy-negative GCA, or no GCA. A total of 305 TAB reports (173 individuals) were reviewed with bilateral TAB performed in 132 cases. The mean length of TAB in patients with biopsy-positive GCA was 15.5 ± 8.9 mm compared to 10.0 ± 5.4 mm for patients with negative biopsies (P = .07). A TAB size > 10 mm had a sensitivity of 50% but only 31% for biopsies between 6 and 10 mm long (P = .003). With unilateral biopsies, the histological diagnosis may be missed in 12.5% of GCA cases. This study recommends that TAB be performed bilaterally, and that each specimen should be ≥ 15 mm (because the sample loses 5 mm in length after fixation).
Intimal Hyperplasia in TAB: A Predictor for Neuro-ophthalmic Complications of GCA? (5)
Dr. Damodar Makkuni and colleagues described the correlation between the severity of intimal hyperplasia (IH) and neuro-ophthalmic complications (NOC) in patients with GCA, which can lead to vision loss in approximately 1/4 of patients. The study included 30 patients with positive TAB in whom visual complications were identified through review of case notes. A histopathologist blinded to the clinical details examined these biopsies and scored the degree of IH into 3 grades: Grade 1 was < 50% luminal occlusion due to IH, Grade 2 was 50% to 75%, and Grade 3 > 75% to complete occlusion. The degree of IH was compared to the prevalence of NOC. Ten of 30 patients had NOC; 1/30 had cerebral infarcts, and 1/30 had infarcts and eye involvement. Grade 3 IH was seen in 9/12 with ischemic complications. After adjusting for age, the odds ratio for visual symptoms was 20.8 (95% CI 2.6-210) for each unit increase in IH score. These results underscore the importance of NOC in GCA and indicate that the degree of IH on TAB is strongly related to the presence of NOC. In addition to early steroid therapy, it is essential to perform early TAB in patients with suspected GCA.
New Treatment for Gout
Despite a clear clinical need, no new therapies for gout have been introduced in over 40 years. Febuxostat is a nonpurine selective inhibitor of xanthine oxidase that shows promise for urate-lowering therapy in gout.
Febuxostat (FEB) or Allopurinol (ALLO) for Gout: Interim Results From the EXCEL Study6
Dr. Michael Becker presented results of this open-label extension study conducted to evaluate treatment response, defined by serum urate (sUA) < 6.0 mg/dL, in 735 patients with gout and baseline sUA > 8.0 mg/dL treated with FEB or ALLO for ≥ 24 months. Patients completing 2 phase III trials of FEB and ALLO were randomized to receive treatment with either FEB 80 mg or 120 mg or ALLO 300 mg (or 100 mg in 4 subjects with baseline serum creatinine ≥ 1.5 mg/dL). Changes in dose and/or urate-lowering medication were permitted during the first 6 months to maintain sUA between 3.0 and 6.0 mg/dL, manage AEs, or at investigator discretion. Subjects with sUA ≥ 6.0 mg/dL at month 6 were therapeutic failures and were discontinued. Changes due to treatment failure occurred in 18% (54/299) of FEB 80 mg, 8% (22/291) of FEB 120 mg, and 57% (82/145) initially receiving ALLO. Overall, 67% (55/82) of subjects initially assigned to ALLO were successfully treated with FEB. Thirty-nine subjects initially receiving FEB 120 mg were switched to 80 mg for a sUA < 3.0mg/dL, with 72% (28/39) achieving an sUA between 3.0 and 6.0 mg/dL. The most frequent AEs (≥ 5 events per 100 patient-years [PY]) were upper respiratory tract infections, musculoskeletal and connective tissue or joint-related signs and symptoms, headaches and diarrhea, with rates similar for FEB and ALLO. Serious AEs (SAEs) were similar at 10 events per 100 PY (FEB) and 11 events per 100 PY (ALLO). The most frequently reported SAEs were cardiac disorders at 3 events per 100 PY for both FEB and ALLO. More than half of subjects randomized to ALLO treatment at commonly used doses failed to achieve or maintain sUA < 6.0 mg/dL and were subsequently treated successfully with FEB. These results suggest that FEB may be effective urate-lowering therapy in gout patients either as primary therapy or in patients with inadequate responses to ALLO.
Systemic Lupus Erythematosus
Novel therapies with more selective mechanisms of action and less toxicity are needed to improve the quality of life and outcomes in patients with systemic lupus erythemosus (SLE).
MEDI-545, an Anti-interferon Alpha MAb, Shows Evidence of Clinical Activity in SLE (7)
Dr. Daniel Wallace and colleagues presented results of a phase I, double-blind randomized study evaluating the effect of MEDI-545, an anti-interferon-α (IFN-α) monoclonal antibody (MAb), on disease activity in 50 patients with SLE. A total of 50 patients were treated with 1 of 5 doses of MEDI-545 (0.3 [n = 6], 1.0 [n = 6], 3.0 [n = 6], 10.0 [n = 7], or 30.0 [n = 8] mg/kg) or placebo [n = 17). Based on an analysis of all patients together, those receiving MEDI-545 had a greater reduction in average SLE Disease Activity Index (SLEDAI) at day 56 (5.4 ± 3.0 to 5.0 ± 2.9, P = .48 placebo versus 5.4 ± 3.1 to 4.2 ± 3.2, P = .002 MEDI-545). MEDI-545-treated patients were also more likely, through 84 days of follow-up, to achieve inactive disease (SELENA-SLEDAI = 0, when SELENA-SLEDAI > 0 at baseline) compared with placebo (12% versus 41%, P = .049); have a composite response (improvement in SELENA-SLEDAI ≥ 4 points), 15% versus 43%, P = .143; achieve Physician Global Assessment ≤ 0.5 inches on a 3-inch VAS, 19% versus 45%, P = .110; have fewer flares (worsening of SELENA-SLEDAI ≥ 4 points), 29% versus 3%, P= .017; and have a lower requirement for new disease-modifying agents or rescue corticosteroid therapy, 35% versus 6%, P = .013. The safety profile of MEDI-545 was acceptable and MEDI-545 was well tolerated. These data confirm that IFN plays an important role in the pathophysiology of SLE and support the efficacy and safety of this potential new therapeutic option.
Randomized Placebo-Controlled Trial of Omega-3-Polyunsaturated Fatty Acids in SLE (8)
Dr. Stephen Wright and colleagues conducted a 24-week randomized, double-blind, placebo-controlled parallel trial to evaluate the clinical effect of dietary supplementation with low-dose omega-3-polyunsaturated fatty acids (fish oil) on disease activity and endothelial function in 60 patients with SLE. There were significant improvements at 24 weeks in the revised Systemic Lupus Activity Measure (SLAM-R) from 9.4 ± 3.0 to 6.3 ± 2.5, P < .001); in British Isles Lupus Assessment Group index of disease activity for SLE (BILAG), from 13.6 ± 6.0 to 6.7 ± 3.8, P < .001; in endothelial function using flow-mediated dilation of the brachial artery from 3.0% (-0.5, -8.2) to 8.9% (1.3, -16.9), P < .001; and in platelet 8-isoprostanes from 177 pg/mg protein (23-387) to 90 pg/mg protein (32-182), P = .007. Low-dose dietary supplementation appears to have a beneficial therapeutic effect on disease activity, improve endothelial function, and decrease oxidative stress in patients with SLE.
Cardiovascular Disease in Rheumatoid Arthritis (RA)
The risk of MI is increased in patients with RA, an effect mediated by the RA disease process or, potentially, by RA therapies.
Effect of Rheumatic Disease Treatment on the Risk of Myocardial Infarction (MI) (9)
Drs. Fred Wolfe and Kaleb Michaud evaluated a longitudinal data bank to determine the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-TNF therapy on the risk of MI in 22,818 incident cases of MI between 1998 and 2006. This included 17,712 patients with RA and 5081 with noninflammatory rheumatic disorders (NIRD). Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (RR) and was further adjusted for age, sex, and baseline values of Health Assessment Questionnaire (HAQ), prednisone use (in RA only), and cardiovascular risk factors (CVRF) (ie, hypertension, diabetes, smoking history, and prior MI). MI was increased in RA compared with NIRD: RR 1.6 (95% CI 1.1-2.1) and was strongly associated with baseline HAQ score, prednisone use, hypertension, diabetes, previous MI, and lifetime smoking exposure. Compared with all other COX-2 inhibitors, NSAIDs, and nontreated patients, the RR for MI for NSAIDS based on multivariable analysis were:
- Rofecoxib 2.8 (1.9, 4.2)
- Valdecoxib 2.3 (1.1, 4.3)
- Celecoxib high-dose 1.6 (1.1, 2.3)
No effect was noted for naproxen, diclofenac, ibuprofen, or acetaminophen. A nonsignificant trend for increased MI risk was seen with higher COX-2 doses (high versus low rofecoxib, P = .069, celecoxib high versus low P = .177). Anti-TNF therapy was used by 56.2% of RA patients (adalimumab 9.0%, etanercept 33.6%, infliximab 40.3%). All anti-TNF agents were associated with a reduced risk of MI RR 0.7 (0.5-0.9) after adjusting for baseline HAQ, prednisone use, hypertension, diabetes, and lifetime smoking exposure. An increased adjusted RR (1.3) of MI was also seen in patients treated with prednisone. These findings suggest that RA therapies may contribute to MI risk in RA patients, both positively and negatively, and highlight the unappreciated risk of glucocorticoid use in this patient population.
Outcomes:
References
- 1. Colbert RA, Turner MJ, DeLay ML, et al. HLA-B27 misfolding activates the IL-23/IL-17 axis via the unfolded protein response in transgenic rats: evidence for a novel mechanism of inflammation. (Platform presentation 1283.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA.
- Koening CL, Langford CA, Kirchner HL, et al. Renal graft survival and patient mortality in Wegener’s granulomatosis (WG): a case/control study. (Platform presentation 702.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA..
- Abdulahad WH, Stegeman CA, Limburg PC, et al. Circulating Pr3-specific T-helper-17 cells in Wegener’s granulomatosis.(Platform presentation 703.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA.
- Breuer GS, Nesher R, Nesher G, et al. Effect of biopsy length and bilateral sampling on the rate of positive temporal artery biopsies. (Platform presentation 704.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA..
- Makkuni D, Wolfe K, Hutchings A, et al. Intimal hyperplasia in temporal artery biopsy a predictor for neuro ophthalmic complications of giant cell arteritis? (Platform presentation 706.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA..
- Becker MA, Schumacher HR, MacDonald PA, et al. Urate-lowering therapy (febuxostat [FEB] or allopurinol [ALLO]) in subjects with gout: interim results from the febuxostat comparative extension long-term study (EXCEL). (Platform presentation 757.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA..
- Wallace DJ, Petri M, Olsen N, et al. MEDI-545, an anti-interferon alpha monoclonal antibody, shows evidence of clinical activity in systemic lupus erythematosus (Platform presentation 1315.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA..
- Wright SA, O’Prey FM, McHenry MT, et al. A randomised placebo-controlled interventional trial of omega-3-polyunsaturated fatty acids on disease activity and endothelial function in systemic lupus erythematosus. (Platform presentation 1317.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA..
- Wolfe F, Michaud K. The effect of rheumatic disease treatment on the risk of myocardial infarction: increased risk from rofecoxib, valdecoxib and celecoxib; decreased risk from anti-TNF therapy. (Platform presentation 1340.) Paper presented at: The Annual Meeting of the ACR/ARHP; November 9, 2007; Boston, MA.
